There is considerable interest in the skin as a site of drug application both for local and systemic effect. However, the skin, and in particular the stratum corneum, poses a formidable barrier to drug and other small molecule penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and increase the range of drugs for which topical and transdermal delivery is a viable option. Enhancement techniques have focused on drug/vehicle optimization such as drug selection, prodrugs and ion-pairs, supersaturated drug solutions, eutectic systems, complexation, liposomes, vesicles and particles. Enhancement via modification of the stratum corneum by hydration, chemical enhancers acting on the structure of the stratum corneum lipids and keratin, partitioning and solubility effects have also been investigated as important parameters for optimization.
A number of drugs and other small molecules may be administered transdermally. Transdermal drug absorption can significantly alter drug kinetics. Transdermal drug absorption depends on a variety of factors including the site of application, thickness and integrity of the stratum corneum epidermidis, size of the molecule, permeability of the membrane of the transdermal drug delivery system, state of skin hydration, pH of the drug, drug metabolism by skin flora, lipid solubility, depot of drug in skin, and alteration of blood flow in the skin by additives and body temperature. The potential for toxic effects of the drug and difficulty in limiting drug uptake are major considerations for nearly all transdermal delivery systems. This is especially true in children because skin thickness and blood flow in the skin vary with age. The relatively rich blood supply in the skin combined with thinner skin has significant effects on the pharmacokinetics of transdermal delivery systems for children. In some situations this may be an advantage, while in others systemic toxicity may result. For example, central nervous system toxicity has been observed in neonates washed with hexachlorophene. The toxicity occurred due to the very thin skin and large body surface area of the neonates, allowing toxic levels to develop from systemic drug absorption.
Transdermal delivery of drugs and other small molecules has been investigated extensively. Some benefits of transdermal drug delivery include the enhancement of the therapeutic effect of the drugs, while minimizing side effects for topical and systemic drug delivery. In topical applications, drugs are delivered to the site of interest with a specific drug concentration. Drugs can also be administrated systemically without hepatic first pass metabolism and dose levels can be stabilized. Most drugs show limited absorption through the skin, because the stratum corneum (SC), the outermost layer of the skin, works as an effective barrier to molecular transport. The SC is composed of corneocytes (dead cells) which are filled with keratin. The intercellular regions within the SC are mainly occupied by neutral lipids. In general, there are three possible pathways for transdermal drug delivery: transport through appendages such as hair follicles, transcellular transport through the corneocytes, and intercellular transport via the extra cellular matrix. In addition to vehicle formulations and chemical enhancers, various physical methods have been investigated so far for transdermal drug delivery. These methods include continuous electric current (iontophoresis), electric pulses (electroporation) and ultrasound (phonophoresis, sonophoresis). These physical methods have an advantage associated with the excellent temporal controllability of drug release. Transdermal drug delivery by laser-induced stress waves (LISWs) has been reported. The LISWs generated by high-power pulsed lasers are characterized by broadband, unipolar and compressive waves. The LISWs interact with tissues in ways that are different from those of ultrasound. The action of ultrasound is primarily mediated by heat and cavitation induced by a negative pressure. The effects of the LISWs are caused by positive mechanical forces. It has been shown in vivo that a single LISW can increase the permeability of the SC. Currently the mechanism of permeabilization of the SC by applying a LISW is not well understood.
The transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms. Transdermal drug delivery offers the controlled release of the drug into the patient. This enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms. In addition, because transdermal patches are user-friendly, convenient, painless, and offer multi-day dosing, it is generally accepted that they offer improved patient compliance. Transdermal patch formulation is an area of continued interest. Because drug-in-adhesive technology has become the preferred system for passive transdermal delivery, two areas of formulation research are focused on adhesives and excipients. Adhesive research focuses on customizing the adhesive to improve skin adhesion over the wear period, improve drug stability and solubility, reduce lag time, and increase the rate of delivery. Because a one-size-fits-all adhesive does not exist that can accommodate all drug and formulation chemistries, customizing the adhesive chemistry allows the transdermal formulator to optimize the performance of the transdermal patch.